It has been recently clarified that TNF-α is an inflammatory cytokine produced by macrophages, macrophage-like cells (Kupffer's cells and microglia), neutrophiles, basophils, eosinophils, lymphocytes, NK cells, LAK cells, mast cells, bone marrow cells, fibroblasts, astrocytes, keratinocytes and the like, and is deeply involved in the onset and pathology of many diseases. The potential establishment of a new treatment method for controlling excess TNF-α has been reported (See, e.g., Black et al., Annual Reports in Medicinal Chemistry, USA, No. 32, pp. 241-250 (1997)).
As regards the correlation between TNF-α and pathology, for example, systemic inflammatory response syndromes including sepsis, septic shock and multiple organ dysfunction syndrome (MODS) are considered to be caused by abnormal production of inflammatory cytokines such as TNF-α, interleukin 1β, interleukin 6 and the like, and neutralization of TNF-α suppresses increase in blood interleukin 1β and blood interleukin 6 (See, e.g., Tracey et al., Nature, UK, No. 330, pp. 662-664 (1987)).
Moreover, a report has documented that insulin resistance induced by obesity can be improved in TNF-α defective animals, which suggests a relationship between TNF-α and non-insulin dependent diabetes mellitus (NIDDM) (See, Uysal et al., Nature, UK, No. 389, pp. 610-614 (1997)).
It has also been clarified in the field of autoimmune diseases that TNF-α affects nerve cells and oligodendrocytes, and plays the role of an effector in neurodegeneration and demyelination (e.g., Suzumura, Igakuno Ayumi, Ishiyaku Publishers, Inc., No. 185, pp. 931-935 (1998)).
Furthermore, detection of a large amount of TNF-α in the synovial fluid of patients with rheumatoid arthritis has also been reported (e.g., Saxne et al., Arthritis & Rheumatism, US, No. 31, pp. 1041-1045 (1998)).
Besides these, the involvement of TNF-α in the etiology of Crohn's disease, fulminant hepatitis, cachexia, bone absorption disease, cardiac infarction, allergic disease and adult respiratory distress syndrome has been pointed out.
Since TNF-α is deeply involved in the onset and aggravation of various diseases, inhibition of the action of TNF-α is considered to enable treatment of those diseases.
While steroid hormone drugs and non-steroidal anti-inflammatory agents are currently utilized for some inflammatory diseases, since they act at various sites and fail to show a specific TNF-α inhibitory action, they may induce harmful side effects. Particularly, the side effects of steroidal agents have themselves become medical problems. An in vitro test report exists, which teaches that a pharmaceutical agent having a phosphodiesterase inhibitory action inhibits TNF-α production. However, its efficacy in living organisms is very weak, to the point that clinical application is considered to be difficult (See, Suzumura, Igakuno Ayumi, Ishiyaku Publishers, Inc., No. 185, pp. 931-935 (1998)). Furthermore, while a treatment using a TNF-α antibody or a soluble TNF-α receptor, which are peptidic polymer compounds, achieved a superior clinical effect in rheumatoid arthritis, Crohn's disease and the like, its treatment effect is not persistent for a long term except in certain patients.
In view of the present situation, the development of a pharmaceutical agent for the prophylaxis or treatment of various diseases considered to be attributable to abnormal TNF-α production, which agent specifically inhibits TNF-α production and which shows a superior treatment effect in living organisms, has been desired.
As a heterocyclic compound, for example, a compound represented by
has been reported (See, Mohamed Hilmy Elnagdi et al., Journal of Chemical Society Perkin) Transaction I, UK, pp. 2667-2670 (1982)), but this reference does not contain any description relating to biological activity. In addition, a compound represented by
has been reported (e.g., JP-A-61-60687), but this reference only describes its activity as a herbicide and does not contain any description relating to TNF-α production inhibitory action.
It is therefore an object of the present invention to provide novel compounds having TNF-α inhibitory activity, methods of using said TNF-α inhibitors, and pharmaceutical compositions and uses of the novel compounds.